Cholangiocarcinoma (CCA) is a highly malignant cancer of the biliary tract with poor prognosis. Consistent with the strong association between bile duct chronic inflammation and cholangiocarcinogenesis, studies from our lab and others have shown that mediators of inflammation, such as prostaglandins (PGs), play an important role in cholangiocarcinogenesis. On the basis of our published studies and new preliminary data, we hypothesize that 15- hydroxyprostaglandin dehydrogenase (15-PGDH) is a key enzyme that suppresses CCA development and progression by converting pro-oncogenic PGE2 to tumor suppressive 15-keto-PGE2. We postulate that induction or reactivation of 15-PGDH expression may represent a promising therapeutic intervention for future prevention and treatment of cholangiocarcinoma. These hypotheses will be examined using complementary approaches of in vitro studies, tumor xenograft models, and mouse models of CCA induction. We will evaluate the impact of 15-PGDH on CCA development in novel mouse models of cholangiocarcinogenesis. We will further dissect the mechanisms that suppress 15-PGDH expression in CCA cells. Experiments will be carried out to evaluate the hypothesis that 15-PGDH is silenced in CCA cells by histone deacetylase (HDAC) via transcriptional suppression and by microRNA-21 (miR-21) via post- transcriptional inhibition. Consequently, we propose experiments to examine the hypothesis that inhibition of HDAC and miR-21 will induce or reactivate 15-PGDH expression and prevent CCA growth. Finally, we will perform studies to evaluate the hypothesis that 15-PGDH induction can sensitize the anti-tumor efficacy of standard CCA chemotherapy. The overall objective of the current application is to dissect the biological functions and molecular mechanisms of 15-PGDH in cholangiocarcinogenesis and to explore new therapeutic options by targeting this pivotal tumor suppressor.